JPH037226A - Remedy for ischemic encephalopathy - Google Patents

Abstract

PURPOSE:To obtain a remedy for ischemic encephalopathy having high safety free from side effects, containing a 3-sulfomoylmethyl-1,2-benzisoxazole derivative or 2-sulfomoylmethylbenzoxazole derivative. CONSTITUTION:A compound shown by formula I (one of X and Y is C and the other is N; R1 is H or halogen; R2 and R3 are H, 1-3C alkyl, 4-methyl-1- piperazinyl) or formula II or an alkali metallic salt thereof is used as it is or blended with a carrier for preparation and pharmaceutically manufactured to give the aimed substance. The substance may be prepared into a dosage form such as tablet, capsule, granule, powder, syrup, injection or suppository. A dose is 0.2-50mg/kg/day and administered dividedly once-several times. The compounds shown by formula I and formula II have strongly anti-cerebral hypoxia sufficiently separated from hypnotic, anesthetic action and is useful for treating diseases in the skull such as cerebral infract or intracerebral hemorrhage.

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a therapeutic agent for ischemic brain damage containing a 3-sulf7moylmethyl-1,2-benziinoxazole derivative or a 2-sulf7moylmethylbenzoxazole derivative as an active ingredient. Conventional technology Unlike other organs, the brain exists in a special environment in which it is submerged in cerebral fluid within a rigid body such as the skull or groin, and is one of the organs with the most active energy metabolism. The rate of oxygen consumption is among the highest of all organs. Most of the energy required by brain neurons is supported by oxygen and glucose, and these energy sources are hardly stored in the brain and are constantly supplied from the blood. Therefore, in order to stably supply an energy source to the brain tissue and maintain a constant external environment for brain neurons, a well-developed mechanism for rArMing cerebral blood flow in cerebral blood vessels itself is well developed. When the homeostatic mechanism of the brain is disrupted by physical pressure such as hematoma, H tumor, or brain trauma, a state of cerebral ischemia occurs, and brain neurons are exposed to a hypoxic state and cannot perform their functions normally. When brain neurons suffer from oxygen-deficient hypoxia (hereinafter referred to as "brain hypoxia J"), the i!i of the brain nerve cell membranes
It causes transient changes, and the infiltration of extracellular fluid causes edema. When cerebral edema increases beyond a certain level, cerebral pressure increases and cerebral circulation disorders occur. The resulting enhancement of cerebral hypoxia, glucose deficiency, and accumulation of its metabolites promote brain edema, further increase cerebral LL cerebral pressure, and cause pressure on the brainstem and impaired passage of cerebrospinal fluid, which further worsens. This forms a vicious cycle of enhanced cerebral hyboxia, accelerated cerebral edema, and increased cerebral pressure. As a result, the lesion expands, even healthy brain tissue develops cerebral hyboxia, resulting in a state of cerebral circulation insufficiency, and the disorder becomes serious. Cerebral hypokinesia is the common denominator for most diseases based on cerebral circulation disorders CEur, Neural, +7 (S
apple. 1,), 113-120 (1978>1).Currently, hypnotic anesthetics such as phenobarbital and thiobarbital are used to treat ischemic brain damage. Since it suppresses nerve activity, the energy demand of the nerve cells themselves is reduced, and a protective effect on nerve cell function is expressed.In other words, hypnotic anesthetics forcefully suppress nerve cell function to a level below normal (M1). By this,
be effective. Therefore, in order to expect the desired effect, it is necessary to administer the drug in an amount that can produce a suppressive effect throughout the central nervous system, and as a result, the respiratory and circulatory systems may be affected by suppression of the respiratory or blood pressure regulating center. Negative effects accompany it as side effects. Therefore, in the treatment of ischemic brain damage, there is a strong desire to develop a drug that does not cause the side effects seen with hypnotic anesthetics and that exhibits excellent therapeutic effects at extremely low doses. The present inventors previously reported that 3-sulfamoylmethyl 1,2-
It was discovered that benzisoxazole Km derivatives and 2-sulfamoylmethylbenzoxazole derivatives have excellent anticonvulsant effects and have weak central nervous system depressant effects, making them effective as antiepileptic agents (for example, Japanese Patent Publication No. 33114/1983). (See issue B+-59308 and US Pat. No. 4,172,896). Purpose of the Present Invention The present inventors have conducted intensive research to find a compound that exhibits an excellent cerebral ischemic protective effect that is not based on the inhibitory effect on neuronal machinery fi1. The present invention was completed by discovering that some of the compounds of Publication No.-59308 (1) satisfy these requirements. Structure and Effects of the Invention According to the present invention, general formula (1) (wherein X and One of Y means a carbon atom, the other means a nitrogen atom, R1 means a hydrogen atom or a halogen atom, R
2 and R3 are the same or different and mean a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, or are bonded to an elementary atom X or Y, (ii) When X is a nitrogen atom and R2 and R3 are hydrogen atoms, R+ means a halogen atom. ) A therapeutic agent for ischemic brain damage is provided, which contains an alkali metal salt of the compound represented by the following or in which R2 and/or R3 are hydrogen atoms as an accompanying component. Specific examples of the halogen atom represented by X in the above formula are:
Examples include fluorine atom, chlorine atom, and bromine atom. Formula (T
Specific examples of the alkali metal salts of the compounds in ) include sodium salts, potassium salts, and lithium salts. The compounds of general formula (I) include the following two types of compounds. (I') (L”
) (in the formula, RIR2 and R3 are the same as those listed above with a bluish tint a) Compound C of formula (1) (hereinafter referred to as "compound of the present invention") and its alkali metal salts are disclosed in Japanese Patent Publication No. 60-33
It can be produced according to the method disclosed in No. 114 and No. 61-59308. Among the compounds of formula (1), suitable compounds include, for example, the following compounds and their sodium salts. All of these are specifically disclosed in the above-mentioned Japanese Patent Publication. 5-fluoro-3-sulf 1 moylmethyl, -1゜2-
Benzisoxazole. 5-chloro-3-sulfuryl-1-moylmethyl-1,2-be7
Zuinoxazole. 5-bromo-3-sul77 moylmethyl-1,2-be7
Zuinoxazole. 5-Fluoro-3-N-ethylsulf7moylmethyl-1,2-benzisoxazole. 5-chloro-3-N-methylsulf 7 moylmethyl-1
, 2-benzisoxazole. 5-Bromo-3-N-methylsulf 7 moylmethyl-1
．． 2-be/duinoxazole. 2-Sulfamoylmethylbenzoxazole. and 5-chloro-2-sul 7-ammoylmethylbenzoxazole The compound of formula (I) and its alkali metal salts are as clear from the following pharmacological experiments:

[Exhibits excellent adhesion activity that supports its applicability as a therapeutic drug for blood-related brain disorders.] That is, the compounds of the present invention and their alkali metal salts exhibit strong protective effects against cerebral hyboxia at very low doses. Furthermore, unlike the hypnotic anesthetics traditionally used to treat ischemic brain disorders, it does not exert a protective effect on nerve cell function by suppressing neural activity in the brain, so it is effective in suppressing the central nervous system as a whole. It does not cause side effects such as respiratory depression or circulatory failure. In addition, while hypnotic anesthetics are limited to administration only in the acute phase, the compounds of the present invention and their alkali metal salts do not exhibit hypnotic anesthetic effects, so they can be used chronically and for the purpose of preventing recurrence of attacks. administration is possible. Furthermore, the compounds of the present invention and their alkali gold rg4 salts have low toxicity and therefore have high safety. Test Example 1 Anti-brain hypoxia effect [Prolongation of mouth opening movement time due to complete ischemia] 11 groups of 5 male STD-ddY mice (body weight 22-26 g) were used. After the required amount of the test compound was uniformly clouded with 0.5% Tora/Togashi fluid, the suspension was orally administered at a rate of 0.1 ml per 1710 g of mouse body. 2 hours after administration,
The neck of the mouse was cut with a decapitation trap, and the duration until the mouth opening movement that appeared in the separated head disappeared was measured. The same volume of 0.5% tragacanth solution was similarly administered to the control group. The dose of test compound required to increase the duration of mouth opening movement by 15% compared to the control group ffi (P Do
s ) was calculated from the dose-effect relationship. The results are shown in Table Ia.
and Ib. The following abbreviations are used in the table to simplify the description. Me: Methyl group Et: Ethyl group Pr: Probyl group Pr(i): Isoprobyl group Table Ia Anti-brain hibikia action Table 1b Brainwashing hibikia worked. After administration, the loss of righting reflex in the mice was measured over time. When the loss of the righting reflex persisted for 60 minutes or more, it was considered a hypnotic anesthetic effect, and the dose ff1 (HDso) that caused the effect in 50% of the animals was calculated using the propi2) method. The results are shown in Table ■. Table ■ Ikubo Anesthetic Effect As is clear from Tables Ia and Ib, Compound 3 of the present invention
．． 6,7. II and 14 showed a stronger brainwashing effect than fumebarbital, and compound 8. 9
．． 10.12 and 18 showed almost equivalent effects. Test Example 2 Hypnotic anesthetic effect 5 to 10 STD-ddY male mice (body weight 22 to 26 g) were used in each group. The required amount of test compound is 0.5
% tragacanth solution, the suspension was orally administered at a rate of 0.1 x 10 per 10 g of mouse body weight') Table I
& represents compound 3 (the same applies below). As is clear from Table 2, the hypnotic anesthetic effect of the compound of the present invention was much weaker than that of fumebarbital. Test Example 3 Acute Toxicity 1 group of 5 to 10 STD-ddY male mice (body m
22 to 26 g) was used. The required amount of test compound is 0.5
% tragacanth solution, and the suspension was orally administered in an amount of 0.2 ml per 10 g of mouse body weight. Animals were observed for 7 days after onset and recovery, and the test compound administration Q (1=DSO> that resulted in the death of 50% of the animals) was calculated by the probit method. The results are shown in Table ■. Table ■ Acute Toxicity 1) Represents compound 3 in Table 1h (the same applies below). As is clear from Table 2, the acute toxicity of the compounds of the present invention was much weaker than that of femebabicur. The compound of formula (1) and its alkali metal salts exhibit a strong anti-brain hypokinesia effect that is sufficiently separated from the hypnotic anesthetic effect, and their toxicity is weak, so they are effective against cranial diseases caused by cerebral ischemia or It can be used to treat various symptoms associated with it.@Specific examples of intraopercular diseases include cerebral infarction M (cerebral thrombosis, cerebral embolism), intracerebral hemorrhage, subarachnoid hemorrhage, 2 head trauma, cerebral M tumor, cerebral meningeal Specific examples of symptoms associated with intracranial disorders include inflammation, cerebral edema, U cognitive impairment, neurological disorder, dementia, subjective syndrome V,
(Dizziness, 1 headache, 1 migraine, nausea, vomiting, etc.), e Increased intracranial pressure during or after surgery. The route of administration may be oral, parenteral or rectal. The role of the compound of the present invention or its alkali metal salt! 5r11 varies depending on the type of compound, route of administration, type of disease, degree of 7 symptoms, age of patient, etc., but is usually 02-5゜q/kg for 7 days, administered once or in several doses. be able to. The compound of the present invention or its alkali metal salt can be used as is,
Alternatively, it is used as a therapeutic agent for ischemic brain damage in the form of a preparation prepared by mixing it with a pharmaceutical carrier. Specific examples of formulations include tablets, capsules, granules, powders, tablets, injections, and small portions. These formulations are prepared according to conventional methods. As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention or its alkali metal salt is used. Tablets, capsules, granules, powders A2
Specific examples of pharmaceutical carriers used for preparation include lactose, lactose, nitol, calcium sulfate, excipients such as crystalline cellulose, sodium carboquine methylcellulose, modified starch, and carpoquine methylcellulose carne. disintegrants such as methylcellulose, gelatin, gum arabic, ethylcellulose, hydroquinepropylcellulose, binders such as polyvinylpyrrolidone, lubricants such as light silicic anhydride, magnesium stearate, talc, hydrogenated oils, etc. Can be mentioned. The tablets may be coated by known methods using coating agents such as carnauba wax, hydroquinepropyl methylcellulose, macrogol, hydroxypropylmethylphthalate cellulose acetate phthalate, white sugar, titanium oxide, nrubitan fatty acid ester, and calcium phosphate. Specific examples of carriers used in the manufacture of Shimitsubu agents include white sugar, glucose, fructose, sweeteners such as nrubit, suspending agents such as gum arabic, tragacanth, sodium carboquine methylcellulose, sodium methylcellulose alginate, crystalline cellulose and vegum, Examples include dispersants such as sorbitan fatty acid ester sodium lauryl sulfate and polysorbate 8o. Syrup 'I
For J4, flavoring agents, fragrances, preservatives, etc. can be added as necessary. You can also dissolve it before use!
''! It may be in the form of a cloudy dry syrup. Specific examples of the base for making the small portions include cacao marigold, saturated fatty acid glycerino ester, glycerogelatin macrogol, etc. When making the small portions, it is necessary to Depending on the situation, a surfactant, a cic acid-containing agent, etc. may be added.Injections are usually prepared by dissolving the alkali metal salt of the compound of the present invention in distilled water for injection, but if necessary, a solubility aid may be added. Agents, buffers, pH adjusters, tonicity agents, soothing agents, preservatives, etc. can be added.Furthermore, the compound of the present invention itself can be suspended in distilled water for injection or vegetable oil for injection. It may be in the form of a preparation, in which case a base, a suspending agent, a thickening agent, etc. may be added as necessary.Also, it may be in the form of a powder or lyophilized product to be dissolved before use. In this case, excipients etc. can be added as necessary.These preparations usually contain the compound of the present invention or its alkali metal salt as an active ingredient at 0.5% or more, preferably 0.5% or more. 1
It can be contained in a proportion of 0 to 70%. These formulations may also contain other therapeutically effective substances as described below. The therapeutic agent for ischemic brain damage of the present invention is glyceol (trademark;
A combination of glycerin/and fructose), cerebral hypotensive agents such as mannitol, vitamin E, and vitamin C. Antioxidants such as vitamins, non-steroidal anti-inflammatory drugs such as indomethacin, ibuprofe/, sulindac, tolmetin, calcium antagonists such as nicardipine, nimodihin, flunaridino, thromboxane antagonists, 5-
It can also be applied in conjunction with other medicines such as lipoxygenase inhibitors and prostagranodi:/I conductors as disclosed in JP-A-59-73522. The present invention will be described in more detail with reference to Examples below, but the present invention is not limited to these Examples. Example 1 Tablet 5-Fluo a-3-sulf 7 moylmethyl-1,2-benzisoxazole ..... 100g milk
Sugar...
・・・・・・ 35g corn starch/starch
・・・・・・・・・ 17g crystalline cellulose
・・・・・・・・・ 40g Hydroxypropyl cellulose No. ψ11... 6g Quality II silicic anhydride
...... 1g Magnenium stearate ...... Ig Among the above components, 5-fluoro-3-sulfamoylmethyl-1,2-
Be/diisoquiosazole, lactose, corn starch/
and crystalline cellulose are mixed, hydroxypropyl cellulose dissolved in water is added and kneaded, and then dried to form granules. This is combined with magnesium stearate and f! Add quality silicic anhydride and compression mold to make 1ti200cm tablet core l000
Lock: A'A. Next, a coating is applied using hydroxypropyl methylcellulose, macrogol, titanium oxide, talc, and light anhydrous silicic acid according to a conventional method to form a film-coated tablet. Example 2 20% defeating agent 2-sulf 7 moylmethylbenzoxazole 2
00g lactose
・・・・・・・・・ 719g Hydroxypropyl cellulose ・・・1◆・・・ 20g Light silicic anhydride ・・・・・・・・・】g When the above components were mixed using a high-speed stirring granulator, 40g of ethylcellulose and 20g of hydroquinepropylcellulose
After spraying 200 g of ethanol-containing if, granulating it, drying and sizing it to make a 20% powder. Example 3 Injection Sodium salt of 5-sulfo-3-sulf 1-moylmethyl-1,2-benzisoxazole...
276g Glycine... 10g 1N Sodium hydroxide... Proper amount 5i! Among the above components, the sodium salt of 5-fluoro-3-sulf7moylmethyl-1,2-be/diisoxazole and glycine are dissolved with stirring in a portion of distilled water for injection, and 1N hydroxylated with stirring)IJ Slowly add umum to adjust pH.
Adjust to 11.5. The remaining distilled water for injection was added, and the resulting solution was filtered through a Me/Blanc filter (0.22 μι), filled into ampoules each with 5 carbon dioxide, purged with nitrogen, melted, and then heated under high pressure at +21'C for 20 minutes. Steam sterilization and injection 1
000 units will be manufactured. Example 4 Injection 2-sulf7moylmethylbenzoxazole 5
00 g Sodium carbonate ・・・・・・
・・211 standard Sodium hydroxide・・・・
・・・ Appropriate amount of propylene glycol ・・・
・・・ 41 Ethanol ・・
・・・・・・ 1110! Among the above ingredients, 2-sulfamoylmethylbenzoxazole, sodium carbonate, propylene glycol, and ethanol were suspended in a portion of distilled water for injection at pH 9.
1N sodium hydroxide is slowly added under stirring until a clear solution of is obtained. Add the remaining distilled water for injection and pass the resulting solution through a membrane filter (0.22μ
After filtration with a filter (Mato), fill in 10 m ampoules and replace with nitrogen.
After melting and sealing, high-pressure steam is applied at +21"C for 20 minutes to make 1000 injections.

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, one of X and Y means a carbon atom, the other means a nitrogen atom, and R_1 represents a hydrogen atom or a halogen atom. means,
R_2 and R_3 are the same or different and mean a hydrogen atom or a linear or branched alkyl group having 1 to 3 carbon atoms, or a group: ▲ has a numerical formula, chemical formula, table, etc. ▼ is 4 -Means methyl-1-piperazinyl group. However, (i) the group: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ is bonded to X or Y, which is a carbon atom, and (ii) X is a nitrogen atom, and R_
When 2 and R_3 are hydrogen atoms, R_1 means a halogen atom. ) or an alkali metal salt thereof as an active ingredient. (2) A compound or its alkali metal represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2 and R_3 are the same as defined in claim 1) The therapeutic agent for ischemic brain damage according to claim 1, which contains a salt as an active ingredient. (3) The therapeutic agent for ischemic brain damage according to claim 2, wherein the active ingredient is 5-fluoro-3-sulfamoylmethyl-1,2-benzisoxazole or an alkali metal salt thereof. (4) The therapeutic agent for ischemic brain damage according to claim 2, wherein the active ingredient is 5-chloro-3-sulfamoylmethyl-1,2-benzisoxazole or an alkali metal salt thereof. (5) The therapeutic agent for ischemic brain damage according to claim 2, wherein the active ingredient is 5-fluoro-3-N-ethylsulfamoylmethyl-1,2-benzisoxazole or an alkali metal salt thereof. (6) Compound or its alkali metal represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2 and R_3 are the same as defined in claim 1) The therapeutic agent for ischemic brain damage according to claim 1, which contains a salt as an active ingredient. (7) The therapeutic agent for ischemic brain damage according to claim 6, wherein the active ingredient is 2-sulfamoylmethylbenzoxazole or an alkali metal salt thereof.